1. Field of the Invention
This invention relates to reactive derivatives of 2-(2-aminothiazol-4-yl)-2-methoxyimino acetic acid and 1H-tetrazol-1-acetic acid of the following general formula I, ##STR3## wherein R.sub.3 = ##STR4##
The present invention also relates to the process for the production thereof as well as to the process for the use thereof in the manufacture of cephalosporin antibiotics such as cefotaxime, ceftriaxone and cefazolin.
2. Discussion of the Background
It is known in the art to synthesize different cephalosporin antibiotics, for instance compounds of formula II which generally comprise of amidification of 7-position of appropriate cephalosporin nucleus with or without substitution at 3.alpha.-position, with the desired addenda. ##STR5## wherein R.sub.1 =H, carboxylic protecting group; ##STR6##
Usually, the synthesis by such known processes of various cephalosporin antibiotics comprises of acylation of 7-aminocephalosporanic acid (7-ACA) or 7-amino desacetoxycephalosporanic acid (7-ADCA) derivatives with a reactive derivative such as an acid chloride, an acid anhydride, an activated ester, etc., of the addendum acid for instance of formulas III and IV. ##STR7##
The above can be described schematically as follows: ##STR8## A number of methods utilizing this concept have been reported for the functionalization of position 7 of the desired cephalosporin nucleus and these are summarized below.
U.S. Pat. No. 4,152,432 describes acylation of 7-ACA with an acid chloride of formula V in which the amino group in the thiazole ring is protected. The amino group is subsequently deprotected generally by hydrolysis or hydrogenolysis. ##STR9##
Because of the inherent inefficiency of amidification of the 7-amino group of cephalosporin nucleus and also of the steps involved in protection and deprotection of the amino group of the thiazolyl ring, the overall yields are low and far from satisfactory. JP 52-102096, JP 53-157596 and GB 2 025 933 utilize the same chemistry--i.e., formation of 2-(2-aminothiazol-4-yl)-2-oxyimino acetyl chloride either with PCl.sub.3, PCl.sub.5, SOCl.sub.2 or POCl.sub.3.
Needless to say, the protection and deprotection of the amino group of the thiazolyl ring are involved in such conventional synthesis techniques for cephalosporin antibiotics.
Besides protection and deprotection of the amino function, the resulting acid chloride, e.g., 2-(2-aminothiazol-4-yl)-2-methoxyimino acetyl chloride, 1H-tetrazol-1-acetyl chloride, is unstable, creating further complication for the synthesis of the desired cephalosporin antibiotics.
U.S. Pat. No. 3,954,745 utilizes the same concept, i.e., formation of 1H-tetrazol-1-acetyl chloride in dimethylacetamide and coupling the acid chloride with the DMF-solvate of the hydrochloride of 7-aminocephalosporin of the following formula VI as shown below to yield cefazolin. ##STR10##
However, yields are low. Also, the acylating agent, 1H-tetrazol-1-acetyl chloride, because of its inherent instability, is difficult to isolate and store at room temperature. Another limitation of this process is that acylation is to be carried out in strictly anhydrous conditions.
U.S. Pat. No. 5,317,099 describes a process for the synthesis of .beta.-lactam derivatives such as cefotaxime and ceftriaxone in which silylated 7-ACA is acylated with acyloxyphosphonium chloride derivative of 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid, which, in turn, is prepared from triphenyl phosphine (TPP), hexachloroethane or carbontetrachloride and 2(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid. Since triphenyl phosphine (TPP) is used as a reactant, the overall cost of coupling the addendum III to the cephalosporin nucleus becomes high.
EP 037,380 describes a process for the synthesis of cephalosporin antibiotics, e.g., cefotaxime and ceftriaxone, which comprises acylation of 7-ACA derivatives with an intermediate of formula VII, ##STR11##
However, the synthesis of the 2-(2-aminothiazol-4-yl)-2-methoxyimino acetic acid benzthiazolyl thioester from 2-(2-aminothiazol-4-yl)-2-methoxyimino acetic acid and bisbenzthiazolyl-(2)!disulfide, involves the use of a costly condensation aid such as triphenyl phosphine (TPP), rendering the whole synthesis very costly.
U.S. Pat. No. 5,037,988 describes a process for the production of cephalosporins, in particular, cefotaxime and ceftriaxone, in which an activated form of an organic acid, i.e., 2-(2-aminothiazol-4-yl)-2-oxyiminoacetylsulfite dialkylformiminium halide hydrohalide of the following formula VIII; ##STR12## is coupled with a 7-aminocephalosporanic acid derivative. The compound of formula VIII was prepared by reacting 2-(2-aminothiazol-4-yl)-2-oximino acetic acid with dimethyl formiminium chloride chlorosulfite of formula IX, which in turn was prepared by reacting approximately equimolar quantities of thionyl chloride and dimethylformamide at room temperature in specific solvents only like benzene or toluene, and hence suffers from a limitation.
However, poor results have been obtained when an attempt was made to prepare the compound of formula IX in solvents such as chloroform and dichloromethane. In these solvents, the compound IX did not separate out in its characteristic form of insoluble oil, as the polarity of these solvents does not allow the formation of these reactants.
Thus, it is evident that the procedures described in the prior art for the preparation of 7-acylamino cephalosporanic acid derivatives are either complex, involving protection or deprotection, or costly, or have other limitations.